Discovery of 3,3'-Spiro[Azetidine]-2-oxo-indoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection

  • ACS Med Chem Lett. 2018 Jan 10;9(2):94-97. doi: 10.1021/acsmedchemlett.7b00418.
Weihua Shi  1 ,  Zhigan Jiang  1 ,  Haiying He  1 ,  Fubiao Xiao  1 ,  Fusen Lin  1 ,  Ya Sun  1 ,  Lijuan Hou  1 ,  Liang Shen  1 ,  Lixia Han  1 ,  Minggao Zeng  1 ,  Kunmin Lai  1 ,  Zhengxian Gu  1 ,  Xinsheng Chen  1 ,  Tao Zhao  2 ,  Li Guo  2 ,  Chun Yang  2 ,  Jian Li  1 ,  Shuhui Chen  1
Affiliations
  • 1. WuXi AppTec (Shanghai) Co., Ltd, 288 FuTe Zhong Road, Shanghai 200131, P. R. China.
  • 2. Buchang Pharmaceutical, 50 Gaoxin Road, Gaoxin District, Xi'an 710075, Shanxi Province, P. R. China.
PMID: 29456794 DOI: 10.1021/acsmedchemlett.7b00418
Abstract

A new series of 3,3'-spirocyclic-2-oxo-indoline derivatives was synthesized and evaluated against respiratory syncytial virus (RSV) in a cell-based assay and animal model. Extensive structure-activity relationship study led to a lead compound 14h, which exhibited excellent in vitro potency with an EC50 value of 0.8 nM and demonstrated 71% oral bioavailability in mice. In a mouse challenge model of RVS Infection, 14h demonstrated superior efficacy with a 3.9log RSV virus load reduction in the lung following an oral dose of 50 mg/kg.